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      Transforming growth factor-β in stem cells and tissue homeostasis

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          Abstract

          TGF-β 1–3 are unique multi-functional growth factors that are only expressed in mammals, and mainly secreted and stored as a latent complex in the extracellular matrix (ECM). The biological functions of TGF-β in adults can only be delivered after ligand activation, mostly in response to environmental perturbations. Although involved in multiple biological and pathological processes of the human body, the exact roles of TGF-β in maintaining stem cells and tissue homeostasis have not been well-documented until recent advances, which delineate their functions in a given context. Our recent findings, along with data reported by others, have clearly shown that temporal and spatial activation of TGF-β is involved in the recruitment of stem/progenitor cell participation in tissue regeneration/remodeling process, whereas sustained abnormalities in TGF-β ligand activation, regardless of genetic or environmental origin, will inevitably disrupt the normal physiology and lead to pathobiology of major diseases. Modulation of TGF-β signaling with different approaches has proven effective pre-clinically in the treatment of multiple pathologies such as sclerosis/fibrosis, tumor metastasis, osteoarthritis, and immune disorders. Thus, further elucidation of the mechanisms by which TGF-β is activated in different tissues/organs and how targeted cells respond in a context-dependent way can likely be translated with clinical benefits in the management of a broad range of diseases with the involvement of TGF-β.

          Growth factor: Activation in health and disease

          Targeting a critical growth factor involved in bone and other tissue remodeling could help treat osteoarthritis and other skeletal disorders. A team led by Zhou Xuedong from Sichuan University in Chengdu, China, and Xu Cao from the Johns Hopkins University School of Medicine in Baltimore, Maryland, USA, review the ways in which temporal and spatial activation of transforming growth factor-β (TGF-β), a multi-functional signaling molecule, are needed for proper tissue development and regulation of stem cells throughout the body. Looking at the skeletal system in particular, the researchers discuss how TGF-β controls the balance between bone resorption and bone formation. Faulty TGF-β signaling can lead to numerous bone-associated disorders, including rare genetic diseases and metastatic cancers. The authors also summarize clinical efforts to modulate TGF-β with drugs for the treatment of osteoarthritis and other conditions.

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          Most cited references 490

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          Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system.

          Neurogenesis in the mammalian central nervous system is believed to end in the period just after birth; in the mouse striatum no new neurons are produced after the first few days after birth. In this study, cells isolated from the striatum of the adult mouse brain were induced to proliferate in vitro by epidermal growth factor. The proliferating cells initially expressed nestin, an intermediate filament found in neuroepithelial stem cells, and subsequently developed the morphology and antigenic properties of neurons and astrocytes. Newly generated cells with neuronal morphology were immunoreactive for gamma-aminobutyric acid and substance P, two neurotransmitters of the adult striatum in vivo. Thus, cells of the adult mouse striatum have the capacity to divide and differentiate into neurons and astrocytes.
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            TGF-beta signal transduction.

             J Massagué (1997)
            The transforming growth factor beta (TGF-beta) family of growth factors control the development and homeostasis of most tissues in metazoan organisms. Work over the past few years has led to the elucidation of a TGF-beta signal transduction network. This network involves receptor serine/threonine kinases at the cell surface and their substrates, the SMAD proteins, which move into the nucleus, where they activate target gene transcription in association with DNA-binding partners. Distinct repertoires of receptors, SMAD proteins, and DNA-binding partners seemingly underlie, in a cell-specific manner, the multifunctional nature of TGF-beta and related factors. Mutations in these pathways are the cause of various forms of human cancer and developmental disorders.
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              Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment.

              The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow (BM), and of clonogenic skeletal progenitors found in BM stroma, has long remained elusive. We show that MCAM/CD146-expressing, subendothelial cells in human BM stroma are capable of transferring, upon transplantation, the HME to heterotopic sites, coincident with the establishment of identical subendothelial cells within a miniature bone organ. Establishment of subendothelial stromal cells in developing heterotopic BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Subendothelial stromal cells residing on the sinusoidal wall are major producers of Angiopoietin-1 (a pivotal molecule of the HSC "niche" involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of skeletal progenitors in BM sinusoids, and angiogenesis.
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                Author and article information

                Contributors
                +86-028-85503494 , zhouxd@scu.edu.cn
                +410-502-6440 , xcao11@jhmi.edu
                Journal
                Bone Res
                Bone Res
                Bone Research
                Nature Publishing Group UK (London )
                2095-4700
                2095-6231
                31 January 2018
                2018
                : 6
                Affiliations
                [1 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Cariology and Endodontics, West China Hospital of Stomatology, , Sichuan University, ; Chengdu, China
                [2 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Pediatric Dentistry, West China Hospital of Stomatology, , Sichuan University, ; Chengdu, China
                [3 ]ISNI 0000 0001 0807 1581, GRID grid.13291.38, State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Oral Implantology, West China Hospital of Stomatology, , Sichuan University, ; Chengdu, China
                [4 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Orthopedic Surgery, , Johns Hopkins University School of Medicine, ; Baltimore, MD USA
                [5 ]ISNI 0000 0001 2171 9311, GRID grid.21107.35, Department of Pediatrics, , Johns Hopkins University, ; Baltimore, MD USA
                Article
                5
                10.1038/s41413-017-0005-4
                5802812
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                © The Author(s) 2018

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